The efficacy of benzimidazole drugs against Plasmodium falciparum in vitro.
The sensitivities in vitro of Plasmodium falciparum to the benzimidazoles, albendazole, thiabendazole, mebendazole, omeprazole and 2 albendazole metabolites, albendazole sulphone and albendazole sulphoxide, were investigated and compared to those of the commonly used antimalarial drugs chloroquine and quinine. Quinine and chloroquine were the most potent drugs tested (EC50 values of 8 x 10(-9)-6 x 10(-8) mol/L and 5-7 x 10(-9) mol/L, respectively). Thiabendazole, mebendazole, albendazole sulphone and albendazole sulphoxide reached maximum growth inhibitions of 13-36% at the highest concentration tested (1 x 10(-4) mol/L). Albendazole (EC50 range: not achieved-2 x 10(-6) mol/L) and omeprazole (EC50 range: 2-4 x 10(-5) mol/L) were the most effective benzimidazoles. The activity of albendazole was pH dependent, as was that of chloroquine, and variable. Albendazole has its primary mode of action on trophozoites, suggesting that the drug may target parasite tubulin polymerization. Omeprazole, although also primarily effective against trophozoites, had additional activity against schizonts and ring forms, suggesting a distinct or additional parasitic target. Given the variable activity of albendazole and its rapid metabolism in vivo into compounds with even less antimalarial activity, it appears unlikely that this benzimidazole will be useful in the treatment of malaria. The rapid activity and different stage-specific profile of the more soluble benzimidazole omeprazole warrants further investigation.
Skinner-Adams
T S
TS
Department of Medicine, University of Western Australia, Fremantle Hospital, Fremantle, Western Australia. tskinner@uniwa.uwa.edu.au
Davis
T M
TM
Manning
L S
LS
Johnston
W A
WA
D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D002738:Chloroquine / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D006863:Hydrogen-Ion Concentration; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development; D011803:Quinine / Q000494:pharmacology
D000962:Antimalarials; D001562:Benzimidazoles; D002738:Chloroquine; D011803:Quinine